EP1007058A1 - USE OF $i(N)-SUBSTITUTED-1,5-DIDEOXY-1,5-IMINO-D-GLUCITOL COMPOUNDS IN COMBINATION THERAPY FOR TREATING HEPATITIS VIRUS INFECTIONS - Google Patents
USE OF $i(N)-SUBSTITUTED-1,5-DIDEOXY-1,5-IMINO-D-GLUCITOL COMPOUNDS IN COMBINATION THERAPY FOR TREATING HEPATITIS VIRUS INFECTIONSInfo
- Publication number
- EP1007058A1 EP1007058A1 EP98906475A EP98906475A EP1007058A1 EP 1007058 A1 EP1007058 A1 EP 1007058A1 EP 98906475 A EP98906475 A EP 98906475A EP 98906475 A EP98906475 A EP 98906475A EP 1007058 A1 EP1007058 A1 EP 1007058A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- dideoxy
- imino
- glucitol
- tetrabutyrate
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
Definitions
- the present invention relates to methods and compositions for treating hepatitis virus infections, especially hepatitis B virus infections, in mammals, especially humans.
- the methods comprise (1) administering N- substituted- 1 , 5-dideoxy-l , 5-imino-D-glucitol compounds in combination with nucleoside antiviral agents, nucleotide antiviral agents, mixtures thereof, or immunomodulating/-immunostimulating agents, or (2) administering N- substituted- 1 , 5-dideoxy-l , 5-imino-D- glucitol compounds in combination with nucleoside antiviral agents, nucleotide antiviral agents, or mixtures thereof, and immunomodulating/i munostimulating agents.
- Such combinations of anti-hepatitis viral agents show unexpected efficacy in inhibiting replication and secretion of hepatitis viruses in cells of mammals infected with these viruses.
- Hepatitis B Virus is a causative agent of acute and chronic liver disease including liver fibrosis, cirrhosis, inflammatory liver disease, and hepatic cancer that can lead to death in some patients (Joklik, Wolfgang K. , Virology, Third Edition, Appleton & Lange, ⁇ orwalk, Connecticut, 1988 (ISBN 0-8385- 9462 -X) ) .
- effective vaccines are available, there are still more than 300 million people worldwide, i.e., 5% of the world's population, chronically infected with the virus (Locarnini, S. A., et . al .
- hepatitis viruses significant as agents of human disease include Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis Delta, Hepatitis E, Hepatitis F, and Hepatitis G (Coates, J. A. V., et.al., Exp . Opin . Ther. Pa tents (1995) 5 (8) : 747-756) .
- animal hepatitis viruses that are species-specific. These include, for example, those infecting ducks, woodchucks, and mice .
- 5-dideoxy-l also known as 1-deoxynoj irimycin, DNJ
- N-alkyl derivatives are known inhibitors of the N- linked oligosaccharide processing enzymes alpha glucosidase I and II (Saunier et al., J " . Biol . Chem . (1982) 257:14155-14161 (1982); Elbein, Ann . Rev. Biochem . (1987) 56:497-534).
- glucose analogs they also have potential to inhibit glucose transport, glucosyl-transferases , and/or glycolipid synthesis ( ⁇ ewbrun et al . , Arch .
- Glucosidase inhibitors such as N- alkyl - 1 , 5-dideoxy- 1, 5-imino-D-glucitol compounds wherein the alkyl group contains between three and six carbon atoms have been shown to be effective in the treatment of Hepatitis B infection (PCT International Publication WO 95/19172) .
- PCT International Publication WO 95/19172 n-butyl-deoxynoj irimycin (n-butyl -D ⁇ J; N- butyl-l-5-dideoxy-l , 5-imino-D-glucitol) is effective for this purpose (Block, T. M., Proc . Natl . Acad. Sci . USA (1994) 91:2235-2239; Ganem, B.
- N-butyl -D ⁇ J has also been tested as an anti-HIV-1 agent in HIV infected patients, and is known to be well tolerated.
- Another alpha glucosidase inhibitor, deoxynoj irimycin (D ⁇ J) has been suggested as an antiviral agent for use in combination with N- (phosphonoacetyl) -L-aspartic acid (PALA) (WO 93/18763) .
- PHA N- (phosphonoacetyl) -L-aspartic acid
- ⁇ -substituted-imino-D-glucitol derivatives and other antiviral agents for the treatment of hepatitis virus infections have not been previously disclosed or suggested.
- Reverse transcriptase inhibitors including the class of nucleoside and nucleotide analogs, were first developed as drugs for the treatment of retroviruses such as human immunodeficiency virus (HIV), the causative agent of AIDS. Increasingly, these compounds have found use against other viruses, including both RNA and DNA viruses, via viral screening and chemical modification strategies. Nucleoside and nucleotide analogs exert their antiviral activities by inhibiting the corresponding DNA and RNA polymerases responsible for synthesis of viral DNA and RNA, respectively. Because viruses contain different forms of polymerases, the same nucleoside/nucleotide compound can have a dramatically different effect against different viruses. For example, lamivudine (3TCTM) appears to be useful against HBV infection, whereas zidovudine
- Toxicity has been significant with some nucleoside analog antivirals.
- nucleoside analog antivirals For example, clinical tests on the use of the nucleoside analog fialuridine (FIAU) for treatment of chronic hepatitis B were suspended recently due to drug-related liver failure leading to death in some patients. Consequently, there is still a need for safer drug regimens for the treatment of hepatitis B infections and hepatitis (Mutchnick, M. G., et . al . , Antiviral Research (1994) 24:245-257).
- FIAU fialuridine
- Immunomodulators and Immunostimulants such as interferon alfa and other cytokines have been used for the treatment of HBV infection with promising results. Unfortunately, the response rates are lower than desired. Interferon treatment is currently approved by the FDA for the treatment of Hepatitis B. Other immune system- affecting drug candidates are presently being investigated. These include thymic pepides for use in the treatment of chronic hepatitis B (CHB) , isoprinosine , steroids, Shiff base-forming salicylaldehyde derivatives such as Tucaresol, levamisol, and the like (Gish, R. G., et.al., Exp . Opin . Invest . Drugs (1995) 4(2): 95-115;
- CHB chronic hepatitis B
- isoprinosine steroids
- Shiff base-forming salicylaldehyde derivatives such as Tucaresol, levamisol, and the like
- N- substituted- imino-D-glucitol compounds and derivatives thereof with other anti -hepatitis virus compounds has, to the present inventor's knowledge, neither been suggested nor disclosed.
- the use of two or more anti-viral agents to provide improved therapy for the treatment of hepatitis B virus infections is desirable due to the morbidity and mortality of the disease.
- Combination therapy is also desirable since it should reduce toxicity in patients as it enables the physician to administer lower doses of one or more of the drugs being given to a patient.
- Combination therapy can also help to prevent the development of drug resistance in patients (Wiltink, E. H.
- the present invention provides a method of treating a hepatitis virus infection in a mammal, comprising administering to said mammal a first amount of an N- substituted- 1 , 5-dideoxy- 1 , 5-imino-D- glucitol compound of Formula I: w
- R is selected from the group consisting of arylalkyl, cycloalkylalkyl , and branched or straight chain alkyl having a chain length of C_ to C 20 , and
- W, X, Y, and Z are each independently selected from the group consisting of hydrogen, alkanoyl, aroyl , and trifluoroalkanoyl ; and a second amount of an antiviral compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, and mixtures thereof , wherein said first and second amounts of said compounds together comprise an anti-hepatitis virus effective amount of said compounds.
- the present invention provides a method of treating a hepatitis- B virus infection in a mammal, comprising administering to said mammal from about 0.1 mg/kg/day to about 100 mg/kg/day of an N- substituted- 1 , 5-dideoxy-l , 5-imino-D-glucitol compound of Formula I, as above, and from about 0.1 mg/person/day to about 500 mg/person/day of a compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral, and mixtures thereof.
- the present invention also provides a method of treating a hepatitis B virus infection in a human patient, comprising administering to said human patient from about 0.1 mg/kg/day to about 100 mg/kg/day of N- (n-nonyl- ) -1 , 5- dideoxy-1 , 5-imino-D-glucitol and from about 0.1 mg/person/day to about 500 mg/person/day of ( - ) -2 ' -deoxy- 3' -thiocytidine-5 ' -triphosphate .
- compositions comprising an N- substituted-1, 5-dideoxy-l , 5-imino-D-glucitol compound of Formula I, as above, and an antiviral compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, and mixtures thereof.
- the invention also provides a pharmaceutical composition, comprising a first amount of an N-substituted- 1 , 5-dideoxy-l , 5-imino-D-glucitol compound of Formula I, as above, and a second amount of an antiviral compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral compound, and mixtures thereof, as well as a pharmaceutically acceptable carrier, diluent, or excipient .
- the invention further provides a pharmaceutical composition for treating a hepatitis B virus infection in a mammal, comprising from about 0.1 mg to about 100 mg of an N- substituted- 1 , 5-dideoxy-l , 5-imino-D-glucitol compound of Formula I, as above, and from about 0.1 mg to about 500 mg of a compound selected from the group consisting of a nucleoside antiviral compound, a nucleotide antiviral, and mixtures thereof .
- compositions for treating a hepatitis B virus infection in a human patient comprising from about 0.1 mg to about 100 mg of N- (n- nonyl- ) -1 , 5-dideoxy-l , 5-imino-D-glucitol , and from about 0.1 mg to about 500 mg of ( - ) -2 ' -deoxy-3 ' -thio ⁇ ytidine-5 ' - triphosphate .
- the present invention also provides methods and compositions like those listed above, wherein the N- substituted- 1 , 5 -dideoxy-1 , 5-imino-D- glucitol compounds of Formula I, nucleoside antiviral compounds, nucleotide antiviral compounds, or mixtures of nucleoside and nucleotide antiviral compounds, are used in combination with immunomodulators, immunostimulators , or mixtures of immunomodulators and immunostimulators .
- the present invention also provides methods and compositions like those listed before the paragraph immediately above, wherein the N- substi tuted-1, 5-dideoxy-l, 5-imino-D-glucitol compounds of Formula I are used in combination with immunomodulators, immunostimulators, or mixtures of immunomodulators and immunostimulators, but without nucleoside antiviral compounds, nucleotide antiviral compounds, or mixtures of nucleoside and nucleotide antiviral compounds.
- Figure 1 shows the anti-hepatitis B virus activity of (-) -2 ' -deoxy-3 ' -thiocytidine-5 ' -triphosphate (3TC) alone and in combination with N-nonyl -DNJ in vi tro .
- Figure 2 shows the plasma concentration of N-nonyl -DNJ versus dose of N-nonyl -DNJ for each animal in Example 4, from samples taken during dosing. Animals are indicated by unique letters, and a small amount of random noise has been added to the dose value so that overlapping values can be distinguished.
- Figure 3 shows the slope of Log(IPDNA + 10) to week versus dose. A distinct letter is used for each animal. The fitted line is from a four parameter logistic model. The parameters of the fitted curve and their approximate standard errors are shown on the plot .
- the present invention thus provides pharmaceutical compositions and methods of treating hepatitis virus infections, especially hepatitis B virus infections, in humans, other mammals, and cells using a combination of an N- substituted- 1 , 5-dideoxy-l , 5-imino-D-glucitol compound with either an antiviral nucleoside, an antiviral nucleotide, mixtures thereof, and/or an immunomodulating or immunostimulating agent.
- the N- substituted- 1 , 5- dideoxy-1 , 5-imino-D-glucitol compounds have basic nitrogen atoms and may be used in the form of a pharmaceutically acceptable salt .
- ⁇ ucleosides and nucleotides useful in the present invention are substituted purine or pyrmidine heterocycles further substituted with R 1 at the 9 position in the case of purines or with R 1 at the 1 position in the case of pyrimidines .
- the immunomodulating and immunostimulating agents useful in the present invention include those that stimulate immune responses effective in controlling or eliminating viruses or other infectious agents. ⁇ on-limiting examples of such immunomodulating and immunostimulating agents include cytokines, peptide agonists, steroids, and classic drugs such as levamisol .
- the drug combinations of this invention may be provided to a cell or cells, or to a human or other mammalian patient, either in separate pharmaceutically acceptable formulations, formulations containing more than one therapeutic agent, or by an assortment of single agent and multiple agent formulations. However administered, these drug combinations form an anti-hepatitis virus effective amount of components.
- anti-hepatitis-virus effective amount refers to a combined amount of (1) an N- substituted- 1 , 5-dideoxy-l , 5-imino-D-glucitol compound with either an antiviral nucleoside, an antiviral nucleotide, a mixture of an antiviral nucleoside and an antiviral nucleotide, or an immunomodulating/ - immunostimulating agent (or mixtures thereof), or (2) a combined amount of an N- substituted- 1 , 5-dideoxy-l , 5-imino- D-glucitol compound with an antiviral nucleoside, an antiviral nucleotide, or a mixture thereof, and an immunomodulating/ -immunostimulating agent (or mixtures thereof) effective in treating hepatitis virus infection.
- the antiviral effectiveness of the aforementioned combinations may involve a variety of different phenomena associated with viral replication and assembly. These may include, for example, blocking hepatitis viral DNA synthesis; blocking viral transcription; blocking virion assembly; blocking virion release or secretion from infected cells; blocking or altering viral protein function, including the function of viral envelope protein(s); and/or the production of immature or otherwise non-functional virions.
- the overall effect is an inhibition of viral replication and infection of additional cells, and therefore inhibition of the progress of infection in the patient.
- N- substituted- 1 , 5-dideoxy-l, 5-imino-D-glucitol compounds useful in the present invention are represented by structure I below:
- R is selected from arylalkyl, cycloalkylalkyl, and branched or straight chain alkyl having a chain length of Ci to C 20/ preferably C 2 to C 14 , more preferably C 6 to C 12 .
- R can also be C_ to C 20 alkyl, preferably C 2 to C 14 , more preferably C 6 to C 12 , containing 1 to 5, more preferably 1 to 3, most preferably 1 to 2, oxygen atoms, i.e., oxa derivatives.
- Preferred R oxa derivatives are 3-oxanonyl, 3-oxadecyl, 7-oxanonyl, and 7-oxadecyl.
- W, X, Y and Z are independently selected from hydrogen, alkanoyl, aroyl, and trifluoroalkanoyl .
- N-substituted-imino-D-glucitol compounds useful in the present invention include, but are not limited to:
- N- (n-decyl- ) -1 5-dideoxy-l , 5-imino-D-glucitol , tetrabutyrate ;
- N- (n-nonyl- ) -1 is N- (n-nonyl- ) -1 , 5-dideoxy-l , 5- imino-D-glucitol and N- (n-nonyl- ) -1, 5-dideoxy-l , 5-imino-D- glucitol, tetrabutyrate.
- the N- substituted- imino-D-glucitol compounds useful in the present invention can be prepared by methods well known in the art as described in, for example, U.S. Patents ⁇ os . 4,182,767, 4,639,436, and 5,003,072, as well as PCT International Publication WO 95/19172 and the references cited therein.
- salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate , digluconate, cyclopentanepropionate, dodecylsulfate , ethanesulfonate , glucoheptanoate , glycerophosphate , hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2 -hydroxy- ethanesulfonate , lactate, maleate, methanesulfonate , nicotinate, 2-naphthalenesulfonate , oxalate, palmoate, pectinate, persulfate, 3 -phenylpropionate, picrate, pivalate, prop
- the basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates such as dimethyl, diethyl, dibuytl, and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides such as benzyl and phenethyl bromides, and others. Water- or oil -soluble or dispersible products are thereby obtained as desired.
- the salts are formed by combining the basic compounds with the desired acid.
- salts can also form salts.
- examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium, or magnesium, or with organic bases or basic quaternary ammonium salts.
- Compounds of the combinations of this invention may be acids or bases. As such, they may be used to form salts with one another.
- the phosphoric acid form of (-) -2 ' -deoxy-3 ' -thiocytidine-5 ' -triphosphate will form a salt with the base form of N- (n-nonyl) -1 , 5-dideoxy- 1, 5-imino-D-glucitol or N- (n-nonyl) - 1 , 5-dideoxy-l , 5-imino- D-glucitol, tetrabutyrate.
- This type of salt can then be provided to the patient in a pharmaceutically acceptable formulation or as a pure single salt.
- the salts can also be used as an aid in the isolation, purification, or resolution of the compounds of this invention.
- Nucleosides and nucleotides useful in the present invention are purine (II) base compounds or pyrimidine (III) base compounds, or analogs such as compounds IV or
- R can be selected from hydroxyalkyl, hydroxyalkenyl , thiolalkyl, alkylthioalkyl , alkoxyalkyl, alkoxyalkenyl , heterocycle, heterocyclo- alkyl, hydroxyalkylalkoxyalkyl , alkoxyalkylalkoxyalkyl , and cycloalkylalkyl .
- the purine compounds can be further substituted at positions 1, 2, 3, 6, 7, or 8 of the purine heterocycle, and the pyrimidine compounds can be substituted at positions 2, 3, 4, 5, or 6 of the pyrimidine heterocycle.
- substituents can be selected from hydroxy, alkoxy, halo, thiol, amino, mono-substituted amino, di-substituted amino, and alkyl.
- alkyl means a straight or branched chain hydrocarbon radical containing from 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms.
- alkenyl means a straight or branched chain hydrocarbon radical having 1 or more double bonds, containing from 2 to 8 carbon atoms, preferably 1 to 4 carbon atoms.
- alkyl means a straight or branched chain alkyl radical containing from six to 14 carbon atoms, preferably seven to 12 carbon atoms, and most preferably eight to 11 carbon atoms.
- aryl alone or in combination with another radical means a phenyl, naphthyl, or indenyl ring, optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, or nitro.
- Alkanoyl means branched or straight chain alkanecarbonyl having a chain length of C_ to C 20 , preferably C 2 to C 14 , more preferably C 4 to C 10 ; "aroyl” means arylcarbonyl ; and " trifluoroalkanoyl “ means alkyl containing three fluoro substituents.
- Halogen means fluorine, chlorine, bromine, or iodine.
- Thiol means sulfur substituted with hydrogen (-SH) .
- Amino means nitrogen with two hydrogen atoms; “monosubstituted amino” and “disubstituted amino” mean amino groups further independently substituted with one or more alkyl or arylalkyl groups.
- Hydroxyalkyl means an alkyl group substituted with one or more hydroxyl groups; "hydroxy- alkenyl” means an alkenyl group substituted with one or more hydroxyl groups; “thioalkyl” means an alkyl substituted with one or more thiol (SH) groups; “alkoxyalkyl” means an alkyl substituted with one or more alkyl ether groups; “alkoxyalkenyl” means an alkenyl group substituted with one or more alkyl ether groups; “hydroxyalkylalkoxyalkyl” means an alkoxyalkyl group substituted with a hydroxyalkyl group; “ alkoxyalkyl - alkoxyalkyl” means an alkoxyalkyl group substituted with an alkoxyalkyl group; “cycloalkylalkyl” means an alkyl group substituted with a cycloalkyl group.
- heterocycle means a saturated or partially unsaturated 5 or 6-membered ring containing one or more oxygen, nitrogen, and/or sulfur heteroatoms .
- Said heterocycle can further be substituted with one to four substituents, which can be independently, hydroxy, hydroxyalkyl, thiol, alkoxy, azido, nitro, a halogen atom, amino, mono- substituted amino, or disubstituted amino.
- Heterocycloalkyl means an alkyl group wherein one or more hydrogen atoms are replaced by a substituted or unsubstituted heterocyclic ring. Also included are the tautomers of the substituents on the compounds of the invention.
- Non- limiting examples of tautomers are ketone/enol tautomers, imino/amino tautomers, N- substituted imino/N- substituted amino tautomers, thiol/thiacarbonyl tautomers, and ring-chain tautomers such as the five and six membered ring oxygen, nitrogen, sulfur, or oxygen- and sulfur- containing heterocycles also containing substituents alpha to the heteroatoms .
- enantiomers and diastereomers as well as racemates and isomeric mixtures of the compounds discussed herein.
- nucleoside and nucleotide compounds useful in the present invention include, but are not limited to:
- D-carbocyclic-2 ' -deoxyguanosine CdG
- dideoxy-cytidine dideoxy-cytosine
- dideoxy-guanine dideoxy-inosine (ddl)
- a preferred compound is ( - ) -2 ' -deoxy-3 ' -thiocytidine- 5' -triphosphate (3TC) .
- nucleoside analogs are generally employed as antiviral agents as is, nucleotides (nucleoside phosphates) must sometimes have to be converted to nucleosides in order to facilitate their transport across cell membranes.
- nucleoside phosphates nucleoside phosphates
- An example of a chemically modified nucleotide capable of entering cells is S-l-3 -hydroxy-2- phosphonylmethoxypropyl cytosine (HPMPC, Gilead Sciences) .
- AA-2G adamantylamide dipeptide 5 adenosine deaminase, Enzon adjuvant, Alliance adjuvants, Ribi adjuvants, Vaxcel
- Anticort antigastrin-17 immunogen Ap antigen delivery system, Vac antigen formulation, IDBC 20 antiGnRH immunogen, Aphton
- CDRI-84-246 35 cefodizime chemokine inhibitors, ICOS
- G-proteins Cadus gludapcin 15 glutaurine glycophosphopeptical
- PEFA-814 20 peptides, Scios peptidoglycan, Pliva
- N- substituted- 1 , 5-dideoxy-l, 5-imino-D-glucitol compounds useful in the present invention can be administered to humans in an amount in the range of from about 0.1 mg/kg/day to about 100 mg/kg/day, more preferably from about 1 mg/kg/day to about 75 mg/kg/day, and most preferably from about 5 mg/kg/day to about 50 mg/kg/day.
- the nucleoside or nucleotide antiviral compound, or mixtures thereof can be administered to humans in an amount in the range of from about 0.1 mg/person/day to about 500 mg/person/day, preferably from about 10 mg/person/day to about 300 mg/person/day, more preferably from about 25 mg/person/day to about 200 mg/person/day, even more preferably from about 50 mg/person/day to about 150 mg/person/day, and most preferably in the range of from about 1 mg/person/day to about 50 mg/person/day.
- Immunomodulators and immunostimulants useful in the present invention can be administered in amounts lower than those conventional in the art.
- thymosin alpha 1 and thymosin fraction 5 are typically administered to humans for the treatment of HepB infections in an amount of about 900 ⁇ g/m 2 , two times per week ⁇ Hepatology (1988) 8:1270; Hepa tology (1989) 10:575; Hepa tology (1991) 14:409; Gastroenterology (1995) 108:A1127).
- this dose can be in the range of from about 10 ⁇ g/m 2 , two times per week to about 750 ⁇ g/m 2 , two times per week, more preferably from about 100 ⁇ g/m 2 , two times per week to about 600 ⁇ g/m 2 , two times per week, most preferably from about 200 ⁇ g/m 2 , two times per week to about 400 ⁇ g/m 2 , two times per week.
- Interferon alfa is typically administered to humans for the treatment of HepC infections in an amount of from about 1 X 10 G units/person, three times per week to about 10 X 10 6 units/person, three times per week (Simon et al .
- this dose can be in the range of from about 0.1 X 10 6 units/person, three times per week to about 7.5 X 10 6 units/person, three times per week, more preferably from about 0.5 X 10 s units/person, three times per week to about 5 X 10 6 units/person, three times per week, most preferably from about 1 X 10 ⁇ units/person, three times per week to about 3 X 10 s units/person, three times per week.
- reduced amounts of other immunomodulators/immunostimulants can be employed in the methods and compositions disclosed herein. Such reduced amounts can be determined by routine monitoring of hepatitis virus in infected patients undergoing therapy. This can be carried out by, for example, monitoring hepatitis viral D ⁇ A in patients' serum by slot-blot, dot- blot, or PCR techniques, or by measurement of hepatitis surface or other antigens, such as the e antigen, in serum.
- Patients can be similarly monitored during combination therapy employing N- substituted- 1 , 5-dideoxy- 1 , 5-imino-D-glucitol compounds and nucleoside and/or nucleotide antiviral agents to determine the lowest effective doses of each.
- doses described above can be administered to a patient in a single dose or in proportionate multiple subdoses .
- dosage unit compositions can contain such amounts of submultiples thereof to make 28 up the daily dose. Multiple doses per day can also increase the total daily dose should this be desired by the person prescribing the drug.
- compositions can be formulated as pharmaceutical compositions. Such compositions can be administered orally, parenterally, by inhalation spray, rectally, intradermally, transdermally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
- parenteral as used herein includes subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John E., Remington ' s Pharmaceutical Sciences , Mack Publishing Co., Easton, Pennsylvania (1975), and Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms ,
- Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 , 3 -butanediol .
- a nontoxic parenterally acceptable diluent or solvent for example, as a solution in 1 , 3 -butanediol .
- acceptable vehicles and solvents that may be employed are water,
- Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed, including synthetic mono- or diglycerides .
- fatty acids 29 such as oleic acid are useful in the preparation of injectables.
- Dimethyl acetamide, surfactants including ionic and non- ionic detergents, and polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful .
- Suppositories for rectal administration of the compounds discussed herein can be prepared by mixing the active agent with a suitable non-irritating excipient such as cocoa butter, synthetic mono-, di-, or triglycerides , fatty acids, or polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature, and which will therefore melt in the rectum and release the drug.
- a suitable non-irritating excipient such as cocoa butter, synthetic mono-, di-, or triglycerides , fatty acids, or polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature, and which will therefore melt in the rectum and release the drug.
- Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
- the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os , the compounds can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone , and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
- Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
- the dosage forms can also comprise buffering agents such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings .
- formulations for parenteral administration can be in the form of aqueous or non- 30 aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
- the compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
- Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
- Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
- Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
- the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the patient and the particular mode of administration.
- Prodrugs are drugs that can be chemically converted in vivo or in vi tro by biological systems into an active derivative or derivatives. Prodrugs are administered in essentially the same fashion as the other pharmaceutical compounds of the invention.
- Non-limiting examples are the esters of the N- substi tuted-1 , 5-dideoxy-l , 5-imino-D-glucitol compounds of this invention.
- Treatment Regimen The regimen for treating a patient suffering from a 31 hepatitis virus infection with the compounds and/or compositions of the present invention is selected in accordance with a variety of factors, including the age, weight, sex, diet, and medical condition of the patient, the severity of the infection, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic , and toxicology profiles of the particular compounds employed, and whether a drug delivery system is utilized. Administration of the drug combinations disclosed herein should generally be continued over a period of several weeks to several months or years until virus titers reach acceptable levels, indicating that infection has been controlled or eradicated.
- patients undergoing treatment with the drug combinations disclosed herein can be routinely monitored by measuring hepatitis viral DNA in patients' serum by slot-blot, dot- blot, or PCR techniques, or by measurement of hepatitis antigens, such as hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) , in serum to determine the effectiveness of therapy.
- hepatitis antigens such as hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg)
- hepatitis B In chronic hepatitis B, for example, remissions are characterized by the disappearance of hepatitis B viral DNA, i.e., reduction to undetectable levels as measured by hybridization tests capable of detecting levels ⁇ 10 5 genomes per ml of serum, and HBeAg from serum despite the continued presence of HBsAg . These serologic events are followed by improvement in the biochemical and histologic features of the disease. The end point of successful treatment in most trials of antiviral therapy is the disappearance of HBeAg and viral
- the treatment regimen/dosing schedule can be rationally modified over the course of therapy so that the lowest amounts of each of the antiviral compounds used in combination which together exhibit satisfactory anti- hepatitis virus effectiveness are administered, and so that administration of such antiviral compounds in combination is continued only so long as is necessary to successfully treat the infection.
- Acetic anhydride (1.08 g, 0.0106 mole) was added to the title compound of Example 1 (0.50 g, 0.0023 mole) in 5 ml pyridine and stirred for 17 days at room temperature .
- the product was evaporated under nitrogen gas.
- the resulting title compound was purified by silica gel chromatography. Structure assignment was supported by NMR, infrared spectra and elemental analysis.
- the accepted IC-90 for 3TC in HepG 2.2.15 (2.2.15) cells is 300nM to 500nM (Doong et al . (1991) Proc . Na tl . Acad . Sci . USA 88:8495-8499) .
- PCR-amplified products were resolved by agarose gel electrophoresis (1.5% agarose), and the 538 nucleotide fragment was quantified by band scanning (HP Jet Imager) .
- the amount of HBV recovered from untreated cells is assumed to be 100%.
- Data from the 6-day time point are presented in Figure 1 as the average values from at least three separate flasks, and the standard error was never greater than 20%, with an average error of 12%.
- N-nonyl -DNJ is greater than that of either compound alone, or the additive individual effects of each compound.
- N-nonyl -DNJ In order to evaluate the efficacy of N-nonyl -DNJ in combination with 3TC (or other nucleoside or nucleotide analogs) against Hepatitis B virus in a woodchuck animal model, an monotherapy experiment using N-nonyl -DNJ alone was first conducted. This was necessary to determine if N-nonyl -DNJ has any anti-HBV effect in the woodchuck and, if N-nonyl -DNJ has a beneficial effect, to design a combination study based on the dose-response relationship of this drug alone.
- N-nonyl -DNJ had no effect on total HBV DNA measurements, which were essentially constant for all dose levels over the pre-dose and dosed portions of the study.
- IPDNA levels were not constant over the study period.
- the low dose animals tended to have increasing levels of IPDNA over the dosing period (weeks 0-4), while high dose animals tended to have decreasing levels of IPDNA over the same period.
- Fitting a straight line to each animal's weekly responses gave a significant difference in the slope of these lines due to either dose or plasma level of drug.
- the plasma levels of drug were also quite variable: animals with the lowest plasma levels in their dose group had lower plasma levels than the animals with the highest plasma levels from the next lower dose group. There were no differences between responses of males and females on any of the measures .
- Plasma Levels There were no clear patterns in the changes in plasma levels of N-nonyl -DNJ which could be related to week of dosing or time since previous dose. Because the plasma levels within an animal seemed reasonably consistent during dosing, the median plasma level for each animal was used for subsequent modeling. The plasma levels for each week of the dosing period are plotted for each animal vs. dose (a small amount of random noise is added to the dose level so points which would lie on top of each other on the plot can be distinguished) (Figure 2) . 37
- a four parameter logistic model is fit with the slope to week as the response and the dose as the predictor. Again, run is considered a block, but because no run has all weeks, it is not possible to fully reflect the blocking in the nonlinear approach. Even so, the nonlinear model yields an EC50 of 7.88 mg/kg/BID dose.
- the average maximum slope observed was 2.71 additional Log (IPDNA ⁇ g/mL) /week, or an increase of about 150%/week, the average minimum slope observed with N-nonyl -DNJ is 0.31 fewer Log(IPDNA ⁇ g/mL) /week) , or about a decrease of about 25%/week.
- the slopes, the fitted model, the parameter estimates from the model, and the approximate standard errors for these parameters are all shown in Figure 3.
- the data indicate an approximate effective monotherapy dose of N-nonyl -DNJ in woodchucks of about 16 mg/kg/day. Whether in woodchucks or humans, the effective dose of both the N-alkyl -DNJ and nucleoside or nucleotide antiviral agent administered in combination therewith can be administered in two equal daily subdoses (i.e., B.I.D.). 3 9
- Figures 2 and 3 show letters to indicate animals.
- Table 2 shows two of the animal codes, the sex, and the dose .
- N-nonyl -DNJ in Combination with 3TC in a Woodchuck Model of Hepatitis B Virus Infection The combined activity of N-nonyl -DNJ and the nucleoside analog 3TC can be assessed using the woodchuck model of hepatitis B virus infection. Twenty-eight woodchucks with persistent woodchuck hepatitis virus (WHV) infection can be utilized. Groups of woodchucks can be treated orally with 3TC alone (s.i.d.), with N-nonyl -DNJ alone (b.i.d.), or with combinations of the two drugs. The antiviral activity of the individual drugs and combinations can be assessed by measuring serum WHV DNA during treatment, and comparing the results of treated groups to placebo treated controls.
- WBV woodchuck hepatitis virus
- Twenty-eight woodchucks with established persistent WHV infection can be used, all of which were experimentally infected with WHV during the first week of life. All can be WHsAg positive at the time the study is initiated.
- a total of eight experimental groups can be used. Woodchucks in each group can be stratified on the basis of gender, body weight, and age. 3TC can be administered orally as an aqueous suspension of Epivir (Glaxo-Wellcome) tablets one time per day. N-nonyl -DNJ can also be administered orally in aqueous solution, in two divided doses. Treatment with both drugs can be followed by the administration of 4 to 5 mis of semisynthetic liquid woodchuck diet to insure complete ingestion of the drugs.
- the experimental groups can be as follows: 41
- Woodchucks can be anesthetized (50mg/kg ketamine, 5mg/kg zylazine) , weighed, and blood samples obtained prior to initial treatment, at weekly intervals during the six week period of treatment, and at 1, 2, and 4 weeks following treatment.
- Serum can be harvested and divided into aliquots.
- One aliquot can be used for analysis of WHV DNA by dot blot hybridization and for WHsAg by ELISA.
- CBCs and clinical biochemical profiles can be obtained prior to treatment and at the end of treatment .
- a second aliquot can be maintained as an archive sample.
- Other aliquots of serum can be used for drug analysis and special WHV DNA analyses .
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US4122197P | 1997-02-14 | 1997-02-14 | |
US41221P | 1997-02-14 | ||
PCT/US1998/003004 WO1998035685A1 (en) | 1997-02-14 | 1998-02-12 | Use of n-substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds in combination therapy for treating hepatitis virus infections |
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EP (1) | EP1007058B1 (en) |
JP (1) | JP2001512462A (en) |
CN (1) | CN100382804C (en) |
AT (1) | ATE295732T1 (en) |
AU (1) | AU6169298A (en) |
DE (1) | DE69830241T2 (en) |
ES (1) | ES2244048T3 (en) |
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US20030100532A1 (en) | 1997-02-14 | 2003-05-29 | Gary S. Jacob | Use of n-substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds in combination therapy for treating hepatitis virus infections |
EP1030839B1 (en) | 1997-11-10 | 2004-02-04 | G.D. SEARLE & CO. | Use of alkylated iminosugars to treat multidrug resistance |
CN1290168A (en) * | 1997-12-11 | 2001-04-04 | 牛津大学院长校长专家委员会 | Inhibition of membrane-associated viral replication |
US6465488B1 (en) | 1997-12-11 | 2002-10-15 | Chancellor, Masters & Scholars Of The University Of Oxford | Inhibition of glycolipid biosynthesis |
EP1714676A3 (en) * | 1998-02-12 | 2006-11-15 | G.D. Searle LLC. | Use of N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds for treating hepatitis virus infections |
MY122185A (en) * | 1998-02-12 | 2006-03-31 | Searle & Co | Use of n-substituted-1, 5-dideoxy-1, 5-imino-d-glucitol compounds for treating hepatitis virus infections |
US6689759B1 (en) | 1998-02-12 | 2004-02-10 | G. D. Searle & Co. | Methods of Treating hepatitis virus infections with N-substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds in combination therapy |
ATE402701T1 (en) * | 1999-02-12 | 2008-08-15 | United Therapeutics Corp | N-(8,8,8-TRIFLUOROOCTYL)-1,5-DIDEOXY-1,5-IMINO- - GLUCITOL FOR THE TREATMENT OF HEPATITIS VIRUS INFECTIONS |
EP1658846B1 (en) * | 1999-02-12 | 2008-07-30 | United Therapeutics Corporation | N-(8,8,8-trifluorooctyl)-1,5-dideoxy-1,5-imino-D-glucitol for treating hepatitis virus infections |
EP1173161A2 (en) | 1999-02-12 | 2002-01-23 | G.D. SEARLE & CO. | Glucamine compounds for treating hepatitis virus infections |
US7256005B2 (en) | 1999-08-10 | 2007-08-14 | The Chancellor, Masters And Scholars Of The University Of Oxford | Methods for identifying iminosugar derivatives that inhibit HCV p7 ion channel activity |
US7816560B1 (en) | 1999-08-10 | 2010-10-19 | Thomas Jefferson University | Long chain n-alkyl compounds and oxa-derivatives thereof |
CN1422156A (en) * | 2000-02-14 | 2003-06-04 | 法马西亚公司 | Use of N-substituted-1,5-dideoxy-1,5-imino-D-glucitol compounds for treating hepatitis virus infections |
WO2004047719A2 (en) * | 2002-09-23 | 2004-06-10 | The Chancellor, Masters And Scholars Of The University Of Oxford | Use of iminosugar derivatives to inhibit ion channel activity |
AU2019339777B2 (en) | 2018-09-12 | 2022-09-01 | Novartis Ag | Antiviral pyridopyrazinedione compounds |
CA3155287A1 (en) | 2019-09-26 | 2021-04-01 | Novartis Ag | Antiviral pyrazolopyridinone compounds |
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CN100382804C (en) | 2008-04-23 |
AU6169298A (en) | 1998-09-08 |
WO1998035685A1 (en) | 1998-08-20 |
EP1007058B1 (en) | 2005-05-18 |
JP2001512462A (en) | 2001-08-21 |
HK1027509A1 (en) | 2001-01-19 |
ES2244048T3 (en) | 2005-12-01 |
DE69830241T2 (en) | 2006-01-26 |
ATE295732T1 (en) | 2005-06-15 |
CN1251993A (en) | 2000-05-03 |
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